This proposal is for a phase I/II fast track project for the STTR program with the main goal to develop a blood test for Alzheimer's disease (AD) diagnosis. AD is the most common dementia in the elderly population and one of the leading causes of death in the developed world. One of the main problems in AD is the lack of an early, sensitive and objective laboratory diagnosis to identify individuals that will develop the disease before substantial brain damage. Compelling evidences point that the hallmark event in AD is the misfolding, aggregation and brain accumulation of amyloid-beta (A?) protein. A? aggregation follows a seeding-nucleation mechanism and involves several intermediates, including soluble oligomers and protofibrils. Recent evidence has shown that A? oligomers are circulating in biological fluids and these structures appear to be key for inducing brain degeneration in AD. Our working hypothesis is that detection of misfolded A? oligomers circulating in blood may be the basis for an early biochemical diagnosis for AD. Our approach is to use the functional property of misfolded oligomers of being capable to catalyze the polymerization of the monomeric protein as a way to detect them. We have recently invented the protein misfolding cyclic amplification (PMCA), which represent a platform technology to detect very small quantities of seeding-competent misfolded oligomeric proteins associated with various protein misfolding diseases. Currently, PMCA has been adapted to detect misfolded prion protein implicated in prion diseases in various biological fluids, including blood and urine and more recently soluble A? oligomers in cerebrospinal fluid of AD patients. The major goal of this project is to adapt the PMCA technology for specific and highly sensitive detection of misfolded A? oligomers in human blood, perform studies of specificity and sensitivity using large number of samples and evaluate the utility of A?-PMCA for pre-clinical identification of people in the way to develop AD. The results generated in this project may lead to the first biochemical test for blood-based diagnosis of AD. The studies included in this project will constitute the basis for regulatory approval of the test that Amprion will commercialize.